Chronic kidney disease (CKD) is a fatal illness, and cardiovascular complications (including arteriovenous (AV) access failure due to venous neointimal hyperplasia (NH) lesions) are the major causes of morbidity and mortality. (Go, A. S. et al., New Engl. J. Med. 351:1296-1305, 2004; Berl, T. and Henrich, W., Clin. J. Am. Soc. Nephrol. 1:8-18, 2006)1;2 The causes of the excess cardiovascular mortality associated with CKD are unknown, since the role of the standard risk factors associated with cardiovascular mortality do not account for the increased risk in CKD (Berl, ibid.).
While AV fistulae constructed with native vessels are the best vascular access available, owing to a lower incidence of stenosis, thrombosis and infection compared with vascular grafts or central venous catheters, even after maturation, the failure rate of 66% at 2 years still remains unacceptable (Shenoy S, et al., J Vasc Surg. 2003; 38(2):229-235.)54 and hemodialysis access related hospitalizations continue to cost well over 1 billion dollars per annum in the United States (Lee H, et al., Am J Kidney Dis. 2002; 40(3):611-622).55 
The cause of AV access failure is predominantly secondary to the occlusive neointimal hyperplastic lesion formation at the anastomosis and/or the outflow veins followed by in situ thrombosis (Mattana J, et al., Kidney Int. 1997; 52(6):1478-1485; Ezzahiri R, et al., Nephrol Dial Transplant. 1999; 14(9):2110-2115; Cinat M E, et al., Ann Vasc Surg. 1999; 13(2):191-198; Tordoir J H, et al., Eur J Vasc Endovasc Surg. 1995; 9(3):305-309).56-59 Unlike restenosis seen with preocclusive atherosclerotic arteries after angioplasty and stenting, neointimal (new intimal) hyperplasia (NH) is seen at the anastomosis involving an artery or a synthetic graft (e.g., ePTFE, Dacron) and a vein in the extremities. Although these blood vessels are usually free of atherosclerotic plaque, they are predisposed to calcification, pre-existing NH and needle stick injuries. Therefore, directional migration of smooth muscle cells (SMCs) into the venous luminal surface is critical to peri-anastomotic NH lesion formation (Roy-Chaudhury P, et al., J Am Soc Nephrol. 2006; 17(4):1112-1127; Nikkari S T, et al., Ann Med. 1994; 26(2):95-100).60,61 
CKD has been implicated in the development of atherosclerosis along with a host of other deranged factors such as hemodynamic forces, inflammatory mediators, platelet activation, coagulation cascade and metabolic factors. Further, there is strong epidemiologic evidence that serum phosphorus is an independent risk factor for cardiovascular events and mortality in CKD (Kestenbaum, B. et al., J. Am. Soc. Nephrol. 16:520-528, 2005; Slinin, Y. et al., J. Am. Soc. Nephrol. 16:1788-1793, 2005).3;4 Serum phosphorus has been linked to another cardiovascular risk factor, vascular calcification (VC) (Kestenbaum et al. 2005; London, G. M. et al., Nephrol. Dial. Transplant. 18:1731-1740, 2003; Raggi, P. et al., J. Am. Coll. Cardiol. 39:695-701, 2002)3;5;6, an important cause of vascular stiffness in CKD. Vascular stiffness from various causes including CKD, atherosclerosis, metabolic diseases, and diabetes, is a major cardiovascular risk factor, leading to increased pulse wave velocity, increased cardiac work, left ventricular hypertrophy, and decreased coronary artery blood flow. (Raggi 2002; Zile, M. R. et al., New Engl. J. Med. 350:1953-1959, 2004; Ohtake, T. et al., J. Am. Soc. Nephrol. 16:1141-1148, 2005).6-8 Phosphorus has been further implicated as a cause of VC through studies in vitro which have demonstrated that it induces phenotypic changes in vascular smooth muscle cells by increasing gene transcription of proteins involved in osteoblast function-bone formation (Tyson, K. L. et al., Arterioscler. Thromb. Vasc. Biol. 23:489-494, 2003)9 and stimulating matrix mineralization (Steitz, S. A. et al., Circ. Res. 89:1147-1154, 2001; Jono, S. et al., Cir. Res. 87:e10-e17, 2000; Reynolds, J. L. et al., J. Am. Soc. Nephrol. 15:2857-2867, 2004)10-12. In the uremic calcifying environment, expression of the contractile proteins of vascular smooth muscle cells, such as α-smooth muscle actin, SM22, and heavy chain myosin, are suppressed (Trion, A. and van der Laarse, A., Am. Heart J. 147:808-814, 2004),13 while osteoblastic lineage markers such as osteocalcin, osteopontin, and the bone morphogenetic proteins 2 and 4 are increased (Tyson 2003; Moe, S. M. et al., Kidney Int'l 61:638-647, 2002; Boström, K. et al., J Clin. Invest. 91:1800-1809, 1993; Dhore, C. R. et al., Arterioscler. Thromb. Vasc. Biol. 21:1998-2003, 2001).9;14-16 Furthermore, the osteoblast specific transcription factor RUNX2, which directs skeletal bone formation (Ducy, P. et al., Cell 89:747-754, 1997),17 is expressed in the vasculature of subjects with end stage CKD (ESKD) (Tyson 2003; Moe, S. M. et al., Kidney Int'l 63:1003-1011, 2003).9;18 
An animal model of CKD-stimulated VC in the atherosclerotic low density lipoprotein receptor-deficient mouse fed high dietary fat has recently been identified (Davies, M. R. et al., J. Am. Soc. Nephrol. 14:1559-1567, 2003).19 The CKD in this model is associated with hyperphosphatemia. It has been demonstrated that the hyperphosphatemia is a direct cause of VC in CKD (Davies, M. R. et al., J. Am. Soc. Neph. 16:917-928, 2005).20 This was the first demonstration in vivo that hyperphosphatemia is causative of a cardiovascular complication of the disease. Furthermore, it has been demonstrated that the skeleton in CKD is a significant contributor of phosphorus to hyperphosphatemia, (Davies 2005; Lund, R, J, et al., J. Am. Soc. Nephrol. 15:359-369, 2004)20;21 along with intestinal absorption of ingested phosphorus and diminished renal excretion. This establishes a direct link between skeletal remodeling and VC in CKD through the serum phosphorus. The mechanism of phosphorus action at the level of the vasculature remains to be demonstrated despite recent progress suggesting direct actions of the ion (Jono 2000; Li, X. et al., Circ. Res. 98:905-912, 2006). 11,22 